Data from FDA - Curated by EPG Health - Last updated 15 August 2018

Indication(s)

1 INDICATIONS AND USAGE NITYR™ is indicated for the treatment of patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. NITYR is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None.
Adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (>1%) are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cycle Pharmaceuticals Ltd. at 1-855-831-5413 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of NITYR has been established based on studies of another oral formulation of nitisinone in patients with HT-1 [see Clinical Studies (14)]. Below is a display of the adverse reactions of nitisinone in these studies. Nitisinone was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. Median duration of treatment was 22 months (range 0.1 to 80 months). The recommended dosage of NITYR is 0.5 mg/kg to 1 mg/kg twice daily [see Dosage and Administration (2.1)]. The most serious adverse reactions reported during nitisinone treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)]. Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in the nitisinone dosage. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%). The most common adverse reactions reported in the clinical trial are summarized in Table 1. *reported in at least 1% of patients; ** another oral formulation of nitisinone TABLE 1 Most Common Adverse Reactions* in Patients with HT-1 Treated with Nitisinone** Elevated tyrosine levels >10% Leukopenia 3% Thrombocytopenia 3% Conjunctivitis 2% Corneal Opacity 2% Keratitis 2% Photophobia 2% Eye Pain 1% Blepharitis 1% Cataracts 1% Granulocytopenia 1% Epistaxis 1% Pruritus 1% Exfoliative Dermatitis 1% Dry Skin 1% Maculopapular Rash 1% Alopecia 1% Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended Dosage (2.1): The recommended initial dosage is 0.5 mg/kg orally twice daily. Titrate the dose based on biochemical and/or clinical response, as described in the full prescribing information. The maximum dosage is 1 mg/kg orally twice daily. Preparation and Administration Instructions (2.2): Maintain dietary restriction of tyrosine and phenylalanine. Take with or without food. For patients who have difficulties swallowing intact tablets, including pediatric patients, the tablets can be disintegrated in water and administered using an oral syringe. If patients can swallow semi-solid foods, the tablets can also be crushed and mixed with applesauce. For preparation and administration instructions, see the full prescribing information. 2.1 Dosage Starting Dosage The recommended starting dosage of NITYR is 0.5 mg/kg orally twice daily. Round up to the nearest dosage that can be administered using the available tablet strengths [see Dosage Forms and Strengths (3)]. Titrate the dosage for individual patients, as needed based on biochemical and/or clinical response. Dosage Titration Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels. If succinylacetone is still detectable one month after the start of nitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily. A maximum dosage of 1 mg/kg orally twice daily may be needed based on the evaluation of all biochemical parameters. Round up to the nearest dosage that can be administered using the available tablet strengths. If the biochemical response is satisfactory, the dosage should be adjusted only according to body weight gain. During the initiation of therapy or if there is a deterioration in the patient’s condition, it may be necessary to follow all available biochemical parameters more closely (i.e., plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity). 2.2 Preparation and Administration Instructions Maintain dietary restriction of tyrosine and phenylalanine when taking NITYR. NITYR can be taken with or without food. For patients, including pediatric patients, who have difficulty swallowing intact tablets, NITYR can be disintegrated in water and administered using an oral syringe. If patients can swallow semi-solid foods, NITYR tablets can be crushed and mixed with applesauce. Administration of NITYR with other liquids or foods has not been studied and is not recommended. Preparation and Administration of NITYR with Water in an Oral Syringe: A 5-mL oral syringe with a cap will be provided by a pharmacist. Follow the instructions below for one or two intact tablets, depending on the number of tablets needed to achieve the patient’s individual dosage. Do not prepare more than two tablets at once within the same oral syringe. If patient’s dosage requires more than two tablets, follow the steps below using multiple oral syringes to achieve the required dose. ​One Tablet Remove the plunger from the 5-mL oral syringe and insert a single, intact tablet. Replace the plunger and draw up 2.6 mL of room temperature water. Invert the syringe and withdraw the plunger to 3 mL. Cap the oral syringe and turn up and down for at least one minute. Then, leave the oral syringe for at least 20 minutes. After 20 minutes, turn the oral syringe up and down for at least one minute. Leave the oral syringe for an additional 30 minutes. Again, turn the oral syringe up and down for at least one minute. Inspect the syringe to ensure the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Turn the oral syringe up and down for one minute to re-suspend the particles. Inspect the syringe again to ensure the the tablet has disintegrated prior to administration to the patient. Do not administer unless the tablet has fully disintegrated. Administer immediately. However, if this is not possible, the suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 2 hours after adding water to the tablets. Discard after 2 hours. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe. Rinse the oral syringe by drawing up 2 mL of water. Invert the oral syringe and withdraw the plunger to 2.6 mL. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully depressing the plunger and ensuring the syringe is empty. Two Tablets Remove the plunger from the 5-mL oral syringe and insert two intact tablets. Replace the plunger and draw up 5 mL of room temperature water. Cap the oral syringe and turn up and down for at least one minute and leave it for at least 20 minutes. After 20 minutes, turn the oral syringe up and down for at least one minute. Leave the oral syringe for an additional 30 minutes. Again, turn the oral syringe up and down for at least one minute. Inspect the syringe to ensure the tablets have disintegrated prior to administration to the patient. Administer immediately. However, do not administer unless the tablet has fully disintegrated. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Before administration of the suspension to the patient, turn the oral syringe up and down for one minute to re-suspend the particles. The suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 2 hours after adding water to the tablets. Discard after 2 hours. Uncap the oral syringe and administer the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe. Rinse the oral syringe by drawing up 2 mL of water. Invert the oral syringe and withdraw the plunger to 2.6 mL. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles. Uncap the oral syringe and administer the suspension into the patient’s mouth, this time fully depressing the plunger and ensuring the syringe is empty. Preparation and Administration of NITYR Mixed in Apples auce For patients who can swallow semi-solid food, NITYR can be crushed and mixed with applesauce: Measure around one teaspoon of applesauce and transfer it into a clean container (e.g., clean glass). Always crush one tablet at a time. Position the tablet between two metal teaspoons and apply light pressure on the top spoon. The two teaspoons should overlap each other to form a fine powder. Press and rotate the two teaspoons against each other repeatedly until all of the tablet is in a fine powder. Carefully transfer the resulting powder to the applesauce container ensuring all the powder is transferred, and no powder residue remains on the teaspoons. If more than one tablet is needed, repeat the procedure starting from Step 2 and collect all the resulting powder together in the applesauce container. Mix the powder into the applesauce until the powder is well dispersed. Administer the entire NITYR-applesauce mixture to the patient’s mouth using a teaspoon. Administer immediately. However, if this is not possible, the mixture can be stored at room temperature, out of direct sunlight, for up to 2 hours after adding the crushed tablets to the applesauce. Discard any mixture that has not been given within 2 hours. To assure that any leftover applesauce mixture from the container is recovered, add around one teaspoon of applesauce to the same container and mix the fresh applesauce with the remaining mixture. Administer the additional NITYR-applesauce mixture immediately to the patient’s mouth using a teaspoon.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have been conducted for nitisinone. In these studies, nitisinone was administered to mice and rabbits during organogenesis with oral doses of nitisinone up to 20 and 8-times, respectively, the recommended initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended initial dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended initial dose, increased gestational length at 4 and 20 times the recommended initial dose, and decreased pup survival at 0.4 times the recommended initial dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended initial dose based on the body surface area. 8.2 Lactation Risk Summary There are no data on the presence of nitisinone in human milk, the effects on the breastfed infant, or the effects on milk production. Data suggest that nitisinone is present in rat milk due to findings of ocular toxicity and lower body weight seen in drug naive nursing rat pups. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NITYR and any potential adverse effects on the breastfed infant from NITYR or from the underlying maternal condition. 8.4 Pediatric Use Pediatric patients with HT-1, ages birth to 17 years have been treated with nitisinone in an open-label, uncontrolled clinical study [see Clinical Studies (14)]. Monitoring of plasma and urine succinylacetone levels are recommended in the pediatric patients to ensure adequate control [see Dosage and Administration (2)]. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine. 8.5 Geriatric Use Clinical studies of nitisinone did not include any subjects aged 65 and over. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.

Interactions

7 DRUG INTERACTIONS CYP2C9 Substrates: Potential for increased systemic exposure of these co-administered drugs, additional monitoring may be warranted. (7.1) 7.1 Interaction with CYP2C9 Substrates If NITYR is co-administered with drugs that are metabolized by CYP2C9, additional monitoring may be warranted because of a potential for increased systemic exposure of these drugs [ see Clinical Pharmacology (12.3) ]. The risk is dependent upon the particular 2C9 substrate and its adverse reaction profile.

More information

Category Value
Authorisation number NDA209449
Agency product number K5BN214699
Orphan designation No
Product NDC 70709-002,70709-000,70709-005
Date Last Revised 25-01-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Cycle Pharmaceuticals Ltd.